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In vivo evidence that bezafibrate prevents oxidative stress and mitochondrial dysfunction caused by 3-methylglutaric acid in rat liver.
- Source :
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Biochimie [Biochimie] 2020 Apr - May; Vol. 171-172, pp. 187-196. Date of Electronic Publication: 2020 Mar 10. - Publication Year :
- 2020
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Abstract
- High urinary excretion and tissue accumulation of 3-methylglutaric acid (MGA) are observed in patients affected by 3-hydroxy-3-methylglutaric (HMGA) and 3-methylglutaconic (MGTA) acidurias. The pathomechanisms underlying the hepatic dysfunction commonly observed in these disorders are not fully elucidated so that we investigated here the effects of intraperitoneal administration of MGA on redox homeostasis, mitochondrial bioenergetics, biogenesis and dynamics in rat liver. The effects of a pre-treatment with the protective compound bezafibrate (BEZ) were also determined. Our data showed that MGA induced lipid peroxidation and altered enzymatic and non-enzymatic antioxidant defenses in liver, indicating redox homeostasis disruption. BEZ prevented most of these alterations induced by MGA. MGA also decreased the activities of the respiratory chain complexes II and IV and increased of II-III, whereas BEZ prevented the alteration in complex II activity. Furthermore, MGA decreased levels of nuclear PGC-1α and Sirt1, and increased levels of AMPKα1 and cytosolic PPARγ, which were blocked by BEZ. MGA augmented the levels of mitofusin-1 and dynamin-related protein 1, suggesting that both fusion and fission mitochondrial processes are enhanced by MGA. BEZ was able to prevent only the changes in mitofusin-1 levels. Collectively, these findings indicate that oxidative stress and mitochondrial dysfunction are mechanisms involved in the hepatic dysfunction found in HMGA and MGTA. It is also presumed that mitochondrial biogenesis stimulation may constitute an attractive approach to reduce MGA toxicity in liver of individuals affected by HMGA and MGTA.<br />Competing Interests: Declaration of competing interest We declare no conflict of interest.<br /> (Copyright © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)
- Subjects :
- Animals
Antioxidants therapeutic use
Chemical and Drug Induced Liver Injury metabolism
Female
Lipid Peroxidation
Liver metabolism
Male
Meglutol metabolism
Mitochondria metabolism
Organelle Biogenesis
Oxidative Stress drug effects
Rats
Rats, Wistar
Bezafibrate therapeutic use
Chemical and Drug Induced Liver Injury drug therapy
Glutarates toxicity
Meglutol analogs & derivatives
Meglutol toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 1638-6183
- Volume :
- 171-172
- Database :
- MEDLINE
- Journal :
- Biochimie
- Publication Type :
- Academic Journal
- Accession number :
- 32169667
- Full Text :
- https://doi.org/10.1016/j.biochi.2020.03.007